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In this work, bioinformatic analysis finds that elevated PCSK9 in HCC correlates with reduced T cell activity and poor prognosis. Based on these discoveries, a PD\u2010L1 nanobody\u2010engineered synthetic RNA virus (\u03b1PDL1\u2010VLPs\/shPCSK9) is fabricated to inhibit PCSK9, thereby restoring MHC\u2010I expression to enhance HCC immunotherapy. The \u03b1PDL1\u2010VLPs\/shPCSK9 is produced using MS2 virus\u2010like particles (VLPs) in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (\n                    <jats:italic>E. coli<\/jats:italic>\n                    ), displaying PD\u2010L1 nanobodies and encapsulating PCSK9\u2010downregulating shRNA. Notably, \u03b1PDL1\u2010VLPs\/shPCSK9 upregulates MHC\u2010I to enhance cytotoxic T lymphocytes (CTLs) recognition of tumor cells while promoting M2\u2010to\u2010M1 macrophages polarization, thereby boosting immunotherapy. In vivo studies indicate that \u03b1PDL1\u2010VLPs\/shPCSK9 exhibits HCC tumor\u2010targeting behavior, suppressing primary tumor growth while avoiding systemic toxicity. Immunological analysis confirms that \u03b1PDL1\u2010VLPs\/shPCSK9 enhances CTLs activation and infiltration, triggering systemic antitumor immunity to eradicate distant tumors. Overall, these findings highlight \u03b1PDL1\u2010VLPs\/shPCSK9 as a promising therapeutic strategy for reversing the multiple immunosuppressive characteristics of HCC, providing a streamlined yet comprehensive approach to potentiate immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/exp2.70226","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:32:46Z","timestamp":1791347566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A PD\u2010L1 Nanobody\u2010Engineered Synthetic RNA Virus Enhances Hepatocellular Carcinoma Immunotherapy by Interfering PCSK9 and Upregulating MHC\u2010I"],"prefix":"10.1002","author":[{"given":"Chuyu","family":"Huang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Molecular Target &amp; Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, the School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Ye","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Molecular Target &amp; Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, the School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Guo","sequence":"additional","affiliation":[{"name":"GMU\u2010GIBH Joint School of Life Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozheng","family":"Liao","sequence":"additional","affiliation":[{"name":"GMU\u2010GIBH Joint School of Life Sciences Guangzhou Medical University  Guangzhou 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